1. Field of the Invention
The present invention is generally directed to pyrrolidin-2-one derivatives and methods and compositions that employ such compounds. In particular embodiments, the compounds are useful as agonists of the DP1 receptor.
2. Background of the Related Art
Prostaglandins (PGs), members of the prostanoid family, are formed by the actions of cyclooxygenases 1 and 2 on arachidonic acid. The biological activities of PGs include, for example, contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inhibition of lipolysis, inhibition of gastric secretion, inhibition of inflammatory mediator release (Coleman et al., Prostanoids and Their Receptors. In Comprehensive Medicinal Chemistry, vol. 3 Ed. J. C. Emmett, 643-714, Pergammon Press, Oxford, UK, 1990) that are mediated by different receptor subtypes. To date, there are at least 8 known receptors that mediate the action of PGs. PGE2 has 4 receptor subtypes (EP1-4 receptors), whereas PGs D2, F2, I2, and thromboxane (TX) A2 each have a single receptor (DP, FP, IP, and TP receptors, respectively; Narumiya et al., Physiol Rev. 79:1193-1226 1999). Further descriptions of these receptors may be found in e.g., U.S. Pat. Nos. 5,606,814 and 5,759,789.
Studies from knock-out mice lacking each type and sub-type of the EP receptor are instructive with respect to the roles of different prostaglandin receptors. For example mice lacking EP receptors showed different roles for the various different types and subtypes of EP receptors (Ushikubi at al. Jpn. J. Pharmacol., 83, 279-285, 2000) in various mechanisms such as ovulation, blood pressure control, closure of ductus arteriosus and bone resorption. Additional roles of EP receptors have been reported such as smooth muscle relaxation in cat trachea for EP2, vasodilatation for EP4 (Gardinier, Br. J. Pharmac. 1986, 87, 45-56; Coleman et al. 1994 Pharmacological Reviews 46 (2), 205-229) and anti-inflammatory activity for EP4 (Takayama et al., The Journal of Biological Chemistry, 277, 46, 44147-44154, 2002). Renal Prostaglandin E2 (PGE2) is crucial for normal renal function by dilating the glomerular microcirculation and vasa recta, supplying the renal medulla and modulating salt and water transport in the distal tubule. There are multiple (at least two) receptor types for DP. Studies similar to the EP receptor studies would be instructive on the roles of the different DP receptors.
Prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor. Consequently, selective effects on one of the sub-types of the EP receptor is difficult to achieve with the endogenous prostaglandins.
Certain prostanoid receptors and modulators of those receptors have been largely reported (Eicosanoids: From Biotechnology to Therapeutic Applications (Plenum Press, New York); Journal of Lipid Mediators and Cell Signalling 14: 83-87 (1996); The British Journal of Pharmacology, 112: 735-740 (1994); WO 96/06822; WO 97/00863; WO 97/00864; WO 96/03380; EP 752421; U.S. Pat. Nos. 6,211,197, 4,211,876; 3,873,566; and Bennett et al. J. Med. Chem., 19 (5): 715-717 (1976).
Certain prostaglandin ligands and analogs have been reported to provide biological activity associated with prostaglandins (U.S. Pat. Nos. 6,288,120; 6,211,197; 4,090,019; 4,033,989; 4,003,911). E-type prostaglandin effects have been reported to be mediated through interaction with the prostaglandin E receptor(s). Certain compounds also have been reported as EP4 agonists (WO 02/24647, EP1110949A1, W003/009872 and WO 03/007941).
It would be desirable to have new compounds and methods for treatment of diseases and disorders associated with the prostaglandin family of compounds.